USRE33495E - Stereoselective preparation of 3-substituted-4-anilino-piperidine compounds and derivatives - Google Patents
Stereoselective preparation of 3-substituted-4-anilino-piperidine compounds and derivatives Download PDFInfo
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- USRE33495E USRE33495E US07/413,427 US41342789A USRE33495E US RE33495 E USRE33495 E US RE33495E US 41342789 A US41342789 A US 41342789A US RE33495 E USRE33495 E US RE33495E
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- lower alkyl
- iaddend
- iadd
- alkyl
- phenyl
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- -1 3-substituted-4-anilino-piperidine compounds Chemical class 0.000 title claims description 17
- 230000000707 stereoselective effect Effects 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 150000002466 imines Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 8
- 239000000543 intermediate Substances 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 230000000269 nucleophilic effect Effects 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 150000001351 alkyl iodides Chemical class 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 3
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 150000004985 diamines Chemical class 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 description 2
- IUKQLMGVFMDQDP-UHFFFAOYSA-N azane;piperidine Chemical compound N.C1CCNCC1 IUKQLMGVFMDQDP-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 150000004753 Schiff bases Chemical group 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- GGNALUCSASGNCK-UHFFFAOYSA-N carbon dioxide;propan-2-ol Chemical compound O=C=O.CC(C)O GGNALUCSASGNCK-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VHXNDLUDRKRBCQ-KALLACGZSA-N n-[(3r,4s)-1-[2-(4-ethyl-5-oxotetrazol-1-yl)ethyl]-3-methylpiperidin-4-yl]-n-(2-fluorophenyl)-2-methoxyacetamide;hydrochloride Chemical compound Cl.O=C1N(CC)N=NN1CCN1C[C@@H](C)[C@@H](N(C(=O)COC)C=2C(=CC=CC=2)F)CC1 VHXNDLUDRKRBCQ-KALLACGZSA-N 0.000 description 1
- LKRMTUUCKBQGFO-UHFFFAOYSA-N n-phenylpiperidin-4-amine Chemical compound C1CNCCC1NC1=CC=CC=C1 LKRMTUUCKBQGFO-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Definitions
- the present invention relates to a stereoselective tandem substitution and reduction reaction of .[.4-(cinalino) piperidine.]. .Iadd.4-anilino-piperidine .Iaddend.derivatives.
- the resulting 3,4-cis compounds are useful intermediates leading to intravenous analgesics.
- U.S. Pat. No. 4,584,303 discloses a method of preparing compounds of the following formula: ##STR1## wherein R 1 is .[.a lower alkyl, lower cyclic alkyl, lower alkyl lower cyclic alkyl, lower alkenyl, lower alkyl phenyl.]. .Iadd.hydrogen or methyl.Iaddend.; R 2 is phenyl or .[.aromatic heterocycle ring either of which may be.]. .Iadd.phenyl .Iaddend.substituted; and R 3 may be a variety of groups including .[.alkyl phenyl.]. .Iadd.phenyl alkyl.Iaddend.. With respect to the R 1 and NHR 2 substituents, it is desirable to obtain the more pharmacologically active cis isomer.
- the invention is directed to a method of preparing a compound of the following formula: ##STR2## wherein R 1 is lower alkyl, lower .[.cylic.]. .Iadd.cyclic .Iaddend.alkyl, .[.lower alkyl.].
- R 2 is a phenyl or aromatic heterocycle ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations thereof; and R 3 can be a wide variety of groups, for example, selected from phenyl lower alkyl, thiazolyl lower alkyl, which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-5-oxo-1H-tetrazol-1-yl) lower alkyl, which can be substituted in the 4-position with a lower alkyl, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof
- an aryl imine precursor is capable of being stereoselectively substituted in a single reactor without requiring intermediate separations or purifications.
- Readily available starting materials are utilized and no special protection of the piperidine nitrogen is necessary.
- Very high selectivity of the cis isomer typically 96%) can be achieved, resulting in an easier purification at an early stage of the overall synthetic route leading to the final product. Production of the nonrecyclable trans isomer is minimized.
- R 1 is lower alkyl, lower cyclic alkyl, .[.lower alkyl.]. lower cyclic alkyl .Iadd.lower alkyl.Iaddend., lower alkenyl, or .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.].;
- R 2 is a phenyl or aromatic heterocycle ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations thereof;
- R 3 is selected from a wide variety of groups, including phenyl lower alkyl, thiazolyl lower alkyl, which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-5-oxo-1H-tetrazol-1-yl) lower alkyl, which can
- lower alkyl, lower alkoxy, lower cyclic alkyl, or lower alkenyl are meant branched or unbranched chain groups with seven or less carbon atoms and preferably 5 or less carbons.
- aromatic heterocycle ring is meant a fully unsaturated ring having 5 or 6 members including 0-3 nitrogen atoms and 0-2 oxygen or sulfur atoms.
- halogen is meant to include fluoro, chloro, bromo, or iodo substituents.
- R 1 groups examples include methyl, ethyl, cyclopropyl, cyclopropylmethyl, allyl and benzyl.
- R 2 groups examples include phenyl, 2-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, pyrazolyl, or thienyl.
- R 3 groups examples include phenyl ethyl, .Iadd.benzyl, .Iaddend.2-(4-ethyl-4-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl, and 2-(4-methyl-thiazoyl)ethyl.
- N-substituted-3-substituted-4-piperidone intermediate compound conventionally employed, for example, in the prior art synthetic route of U.S. Pat. No. 4,584,303.
- This latter compound is difficult to make.
- Applicants' above described reaction scheme begins with the intermediate compound N-substituted-4-piperidone, which is commercially available from Aldrich Chemical Co. (Milwaukee, Wis.) or Chemical Dynamics Corp. (So. Plainfield, N.J.) or else easily made by a Mannich condensation, as will be readily appreciated by those skilled in the art.
- the latter piperidone compound is then reacted with a substituted or unsubstituted phenyl amine or aromatic heterocyclic amine to form the imine precursor .[.(III).]. .Iadd.(II) .Iaddend.above.
- This reaction is suitably carried out in the presence of p-toluene sulfonic acid and refluxed while collecting water.
- the imine precursor .[.(III).]. .Iadd.(II) .Iaddend. is then stirred at a low temperature with a non-nucleophilic base such as freshly prepared lithium diisopropyl amide in order to deprotonate the imine.
- Non-nucleophilic bases include LDC (lithium dicyclohexylamide), LIC (lithium isopropylcyclohexylamide), LTP (tetramethylpiperamide) and LHS [lithium bis(trimethylsilyl)]amide.
- substituting agents are iodides, bromides and chlorides. Tosylates and mesylates and other substituting agents known to those skilled in the art are also suitable.
- the most preferred reducing agent is "Super-Hydride”.Iadd., i.e. lithium triethylborohydride, .Iaddend.because of its superior combination of cis selectivity and speed.
- Other preferred hindered borohydride reducing agents include L-selectride (lithium tri-sec-butylborohydride, 1.0 molar in THF) and N ⁇ -Enantride (lithium hydride, a 9- ⁇ N-nopolbenzyl ether adduct, 0.5 molar in THF).
- a cis:trans selectivity of greater than 90 percent and typically 96 percent is thereby obtainable.
- Suitable reducing agents include Red-Al (sodium bis(2-methoxy-ethoxy)aluminum hydride, 3.4 molar in toluene, and LiAlH 4 . Typically, a selectivity of only about 60-70 percent cis:trans is obtained with the latter reducing agents. All of the above named reducing agents are commercially available from Aldrich Chemical Co. (Milwaukee, Wis.).
- a major advantage of the above described synthetic route is that the reactions occur in a single vessel by the sequential introduction of the necessary reactants. Consequently, successive isolations and purifications are obviated, thereby greatly simplifying the overall route to a variety of therapeutic agents, notably of the fentanyl type, which are used in humans for inducing anesthesia or analgesia, for example .[.A-3331.]. .Iadd.cis-1[2-(4-ethyl-4-5-dihydro-5-oxy-1H-tetrazol-1-yl)ethyl]-3-methyl-4-[N-2(2-fluorophenyl methoxyacetamido] piperidine hydrochloride.Iaddend..
- This example illustrates the preparation of .[.1-benzyl-3-(cis-methyl)-4-[N-(20fluorophenyl)amino]piperidine.]. .Iadd.1-benzyl-3-(cis-methyl)-4-(2-fluorophenyl) amino piperidine.Iaddend..
- LDA was prepared under an atmosphere of argon by adding freshly distilled diisopropyl amine, 15 ml (107 mmol) dropwise to a cold (0° C.) solution of 55 mls of 1.6M n-butyllithium (88 mmol) in hexane in 60 mls of anhydrous THF. After 15 minutes at 0° C. the LDA solution was cooled to -78° C. in an isopropanol-dry ice slush bath. The solution of imine .[.1.]. (80.31 mmol) was added dropwise with stirring. The reaction was stirred at -78° C.
- Example 2 In an analogous manner to the synthesis of Example 1, except using 1-iodopropane, benzyl bromide, and (bromomethyl)-cyclopropane, respectively as the substituting agent, the following compounds were prepared: ##STR10## .[.1-benzyl-3-[cis-(n-propyl)]-4-[N-(2-fluorophenyl)amino]-N piperidine.]. .Iadd.1-benzyl-3-[cis-(n-propyl)]-4-2-fluorophenyl)amino piperidine .Iaddend.oil at R.T.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention is directed to an improved stereoselective tandem substitution and reduction of an imine precursor to the cis form of .[.3-substituted-4-(phenylamino)piperidine.]. .Iadd.3-substituted-4-anilino piperidine .Iaddend.compounds or their substituted derivatives.
Description
The present invention relates to a stereoselective tandem substitution and reduction reaction of .[.4-(cinalino) piperidine.]. .Iadd.4-anilino-piperidine .Iaddend.derivatives. The resulting 3,4-cis compounds are useful intermediates leading to intravenous analgesics.
U.S. Pat. No. 4,584,303 discloses a method of preparing compounds of the following formula: ##STR1## wherein R1 is .[.a lower alkyl, lower cyclic alkyl, lower alkyl lower cyclic alkyl, lower alkenyl, lower alkyl phenyl.]. .Iadd.hydrogen or methyl.Iaddend.; R2 is phenyl or .[.aromatic heterocycle ring either of which may be.]. .Iadd.phenyl .Iaddend.substituted; and R3 may be a variety of groups including .[.alkyl phenyl.]. .Iadd.phenyl alkyl.Iaddend.. With respect to the R1 and NHR2 substituents, it is desirable to obtain the more pharmacologically active cis isomer.
The method taught in U.S. Pat. No. .[.3,584,303.]. .Iadd.4,584,303 .Iaddend.for preparing compounds of .Iadd.the above .Iaddend.formula .[.(I).]. requires a multi-step synthetic route involving the preparation of cis isomers at an advanced stage of the synthetic route. Furthermore, a cis:trans ratio of not greater than 70:30 can be achieved.
J. Burke, Jr. et al., J. Med. Chem., Vol. 29, No. 6, pp 1087-1093 (1986), discloses a method to prepare piperidine derivatives, which method suffers the same disadvantages of the above-mentioned prior art method. Furthermore, the multi-step method of Burke et al. requires expensive starting materials and protection of the piperidine nitrogen.
The deprotonation of aliphatic imines followed by alkylation is generally known as, for example, shown by Collum et al., J. Am. Chem. Soc., Vol. 106, pp 4865-4869 (1984). The reduction of an imine is in itself also conventional.
The invention is directed to a method of preparing a compound of the following formula: ##STR2## wherein R1 is lower alkyl, lower .[.cylic.]. .Iadd.cyclic .Iaddend.alkyl, .[.lower alkyl.]. lower cyclic alkyl .Iadd.lower alkyl.Iaddend., lower alkenyl, or .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.].; R2 is a phenyl or aromatic heterocycle ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations thereof; and R3 can be a wide variety of groups, for example, selected from phenyl lower alkyl, thiazolyl lower alkyl, which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-5-oxo-1H-tetrazol-1-yl) lower alkyl, which can be substituted in the 4-position with a lower alkyl, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof.
According to the method of the present invention, an aryl imine precursor is capable of being stereoselectively substituted in a single reactor without requiring intermediate separations or purifications. Readily available starting materials are utilized and no special protection of the piperidine nitrogen is necessary. Very high selectivity of the cis isomer (typically 96%) can be achieved, resulting in an easier purification at an early stage of the overall synthetic route leading to the final product. Production of the nonrecyclable trans isomer is minimized.
Applicants have found an improved method for the efficient and economical preparation of compounds according to formula .[.(I).]. below: ##STR3## wherein R1 is lower alkyl, lower cyclic alkyl, .[.lower alkyl.]. lower cyclic alkyl .Iadd.lower alkyl.Iaddend., lower alkenyl, or .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.].; R2 is a phenyl or aromatic heterocycle ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations thereof; and R3 is selected from a wide variety of groups, including phenyl lower alkyl, thiazolyl lower alkyl, which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-5-oxo-1H-tetrazol-1-yl) lower alkyl, which can be substituted in the 4-position with a lower alkyl, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof.
By the term lower alkyl, lower alkoxy, lower cyclic alkyl, or lower alkenyl are meant branched or unbranched chain groups with seven or less carbon atoms and preferably 5 or less carbons. By aromatic heterocycle ring is meant a fully unsaturated ring having 5 or 6 members including 0-3 nitrogen atoms and 0-2 oxygen or sulfur atoms. The term halogen is meant to include fluoro, chloro, bromo, or iodo substituents.
Examples of suitable R1 groups include methyl, ethyl, cyclopropyl, cyclopropylmethyl, allyl and benzyl.
Examples of suitable R2 groups include phenyl, 2-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, pyrazolyl, or thienyl.
Examples of suitable R3 groups include phenyl ethyl, .Iadd.benzyl, .Iaddend.2-(4-ethyl-4-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl, and 2-(4-methyl-thiazoyl)ethyl.
The route to compounds of the .[.formula (I).]. .Iadd.invention .Iaddend.proceeds as follows: ##STR4## wherein R1, R2 and R3 are as defined above and R1 X is a reagent capable of adding the R1 group to the 3 position of the piperidine ring, for example, a lower alkyl iodide alkylating agent.
It is noted that the present invention does not involve the N-substituted-3-substituted-4-piperidone intermediate compound conventionally employed, for example, in the prior art synthetic route of U.S. Pat. No. 4,584,303. This latter compound is difficult to make. Instead, Applicants' above described reaction scheme begins with the intermediate compound N-substituted-4-piperidone, which is commercially available from Aldrich Chemical Co. (Milwaukee, Wis.) or Chemical Dynamics Corp. (So. Plainfield, N.J.) or else easily made by a Mannich condensation, as will be readily appreciated by those skilled in the art. The latter piperidone compound is then reacted with a substituted or unsubstituted phenyl amine or aromatic heterocyclic amine to form the imine precursor .[.(III).]. .Iadd.(II) .Iaddend.above. This reaction is suitably carried out in the presence of p-toluene sulfonic acid and refluxed while collecting water. The imine precursor .[.(III).]. .Iadd.(II) .Iaddend.is then stirred at a low temperature with a non-nucleophilic base such as freshly prepared lithium diisopropyl amide in order to deprotonate the imine. Other suitable non-nucleophilic bases include LDC (lithium dicyclohexylamide), LIC (lithium isopropylcyclohexylamide), LTP (tetramethylpiperamide) and LHS [lithium bis(trimethylsilyl)]amide.
By removal of the alpha (to the schiff base) proton, the following anion is generated: ##STR5##
Addition of a substituting agent R1 X such as the alkylating agent alkyl iodide results in the anion .[.IIIa.]. .Iadd.(IIa) .Iaddend.attaching the electrophile R1 X to form the following alkylated imine intermediate. ##STR6##
The most preferred substituting agents are iodides, bromides and chlorides. Tosylates and mesylates and other substituting agents known to those skilled in the art are also suitable.
Finally, without the necessity of isolating .[.(IIIb),.]. .Iadd.the alkylated imine compound (III) .Iaddend.a very selective reduction to the desired valuable intermediate (IV) above is carried out. This reduction is a steric approach control reaction wherein the least crowded side of the .[.intermediate (IIIb).]. .Iadd.alkylated imine compound (III) .Iaddend.is preferably .[.attached.]. .Iadd.attacked .Iaddend.by a relatively highly hindered reducing agent such as the hindered borohydride reducing agents.
The most preferred reducing agent is "Super-Hydride".Iadd., i.e. lithium triethylborohydride, .Iaddend.because of its superior combination of cis selectivity and speed. Other preferred hindered borohydride reducing agents include L-selectride (lithium tri-sec-butylborohydride, 1.0 molar in THF) and Nβ-Enantride (lithium hydride, a 9-ββN-nopolbenzyl ether adduct, 0.5 molar in THF). A cis:trans selectivity of greater than 90 percent and typically 96 percent is thereby obtainable. Other suitable reducing agents include Red-Al (sodium bis(2-methoxy-ethoxy)aluminum hydride, 3.4 molar in toluene, and LiAlH4. Typically, a selectivity of only about 60-70 percent cis:trans is obtained with the latter reducing agents. All of the above named reducing agents are commercially available from Aldrich Chemical Co. (Milwaukee, Wis.).
A major advantage of the above described synthetic route is that the reactions occur in a single vessel by the sequential introduction of the necessary reactants. Consequently, successive isolations and purifications are obviated, thereby greatly simplifying the overall route to a variety of therapeutic agents, notably of the fentanyl type, which are used in humans for inducing anesthesia or analgesia, for example .[.A-3331.]. .Iadd.cis-1[2-(4-ethyl-4-5-dihydro-5-oxy-1H-tetrazol-1-yl)ethyl]-3-methyl-4-[N-2(2-fluorophenyl methoxyacetamido] piperidine hydrochloride.Iaddend.. The remaining steps in the overall synthesis to such compounds are disclosed in detail in U.S. Pat. No. 4,584,303 to Huang et al., which hereby is incorporated by reference. Other compounds which may be prepared by a synthetic route within the scope of the present invention include β-hydroxyl-3-methylfentanyl and cis-3-methyl fantanyl (known in the chemical and pharmaceutical literature as F-7302 and R 26,800, respectively) which have demonstrated potent analgesic activity.
This example illustrates the preparation of .[.1-benzyl-3-(cis-methyl)-4-[N-(20fluorophenyl)amino]piperidine.]. .Iadd.1-benzyl-3-(cis-methyl)-4-(2-fluorophenyl) amino piperidine.Iaddend.. A solution of 1-benzyl-4-piperidone, 15.20 gms (80.31 mmol), 2-fluoroaniline, 9.02 gms (81.17 mmol) and p-toluenesulfonic acid monohydrate, 0.48 gms in 200 ml of toluene was refluxed overnight under argon collecting water in a Dean-Stark trap. After 18 hours the theoretical amount of water had separated and the trap was drained several times to distill off 100 mls of toluene. The reaction was cooled under argon and diluted with 40 mls anhydrous THF. The deep orange solution of crude imine .[.1.]. was used "as is" for next step. ##STR7##
LDA was prepared under an atmosphere of argon by adding freshly distilled diisopropyl amine, 15 ml (107 mmol) dropwise to a cold (0° C.) solution of 55 mls of 1.6M n-butyllithium (88 mmol) in hexane in 60 mls of anhydrous THF. After 15 minutes at 0° C. the LDA solution was cooled to -78° C. in an isopropanol-dry ice slush bath. The solution of imine .[.1.]. (80.31 mmol) was added dropwise with stirring. The reaction was stirred at -78° C. for 1 hour followed by rapid addition of methyl iodide, 12.9 gms (90.88 mmol). The reaction was stirred at -78° C. for 15 minutes followed by warming to room temperature. After 10 minutes at -78° C. a precipitate formed which redissolved as the reaction warmed up. After stirring at room temperature for 2 hours the reaction was cooled to 0° C. in an ice bath and 120 mls. 1.0M .[.Lithium triethlyborohydride.]. .Iadd.lithium triethylborohydride .Iaddend.in THF was added dropwise via syringe. The reaction was stirred overnight (16 hours) warming to room temperature. The reaction was then cooled back down to 0° C. and 50 mls of water was added slowly dropwise (exotherm and vigorous gas evolution). The quenched reaction mixture was concentrated to a pasty oil which was dissolved in 200 mls toluene and washed with 100 mls of water. The toluene layer was separated, dried over anhydrous sodium sulfate and concentrated to give a crude mixture of cis and trans diamine. Analytical LC showed the cis/trans diamine ratio to be 92.2:7.8. This crude oil was flash chromatographed on Silica 60, 230-444 mesh (444 gms) eluting with 1:10 EtOAc/Hex with 0.1% ammonium hydroxide added to give 9.74 gms pure cis diamine (40.6%) shown below and 1.57 gms cis and trans .[.diammine.]. .Iadd.diamine .Iaddend.mixture. Total isolated yield of cis and trans .[.diammine.]. .Iadd.diamine .Iaddend.was 47.2%. ##STR8##
M.P.: 55°-56° C.
NMR: 7.40(s,5H), 7.20-6.35(m,4H), 3.90(br s,1H), 3.40(br s,2H), 3.00-1.30(complex,8H), 0.95(d,3H)
In an analogous manner to the synthesis of Example 1, except using allyl bromide as the substituting agent, the compound .[.1-benzyl-3-(cis-allyl)-4-[N-(2-fluorophenyl)amino]piperidine.]. .Iadd.1-benzyl-3-(cis-allyl)-4-(2-fluorophenyl)amino piperidine .Iaddend.was prepared having the following formula: ##STR9## oil at room temperature
NMR: 7.30 (m,5H), 6.95(m,2H), 6.60(m,2H), 5.65(m,1H), 4.45(m,2H), 3.95(br 2,1H), 3.60(m,1H), 3.50 (ABq,2H), 2.60-1.65(complex,9H)
In an analogous manner to the synthesis of Example 1, except using 1-iodopropane, benzyl bromide, and (bromomethyl)-cyclopropane, respectively as the substituting agent, the following compounds were prepared: ##STR10## .[.1-benzyl-3-[cis-(n-propyl)]-4-[N-(2-fluorophenyl)amino]-N piperidine.]. .Iadd.1-benzyl-3-[cis-(n-propyl)]-4-2-fluorophenyl)amino piperidine .Iaddend.oil at R.T.
NMR: 7.40(s,5H), 7.40-6.50(m,4H), 3.95(br s, 1H), 3.60(m,1H), 3.50(ABq,2H), 2.60-0.30(complex,14H) ##STR11## .[.1-benzyl-3-(cis-benzyl)-4-[N-(2-fluorophenylamino)]piperidine.]. .Iadd.1-benzyl-3-(cis-benzyl)-4-(2-fluorophenyl)amino piperidine .Iaddend.oil at R.T.
NMR: 7.40-6.40(complex,14H), 4.05(m,1H), 3.50(br s,2H), 3.85-1.45(complex,10H). ##STR12## .[.1-benzyl-3-[cis-(cyclopropyl)methyl]-4-[N-(20fluorophenylamino)]piperidine.]. .Iadd.1-benzyl-3-[cis-(cyclopropyl)methyl]-4-(2-fluorophenyl)amino piperidine .Iaddend.oil at R.T.
NMR: 7.50-6.50(m,9H), 4.35(m,1H), 3.40(br s,2H) 3.35-0.80(complex,10H), 0.60-0.05(m,5H)
It will be understood that the embodiments described herein are merely exemplary and that a person skilled in the art may make variations and modifications without departing from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (17)
1. A method of preparing the cis isomer of a 4-anilino-3-R1 -piperidine, wherein R1 is lower alkyl, lower cyclic alkyl, .[.lower alkyl.]. lower cyclic alkyl .Iadd.lower alkyl.Iaddend., .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.]., or lower alkenyl, said method comprising:
(i) depronating a 4-imine piperidine with a non-nucleophilic base to form a deprotonated anion at the 3-position of the piperidine ring;
(ii) reacting said deprotonated anion with a substituting agent to introduce an R1 group in said 3-position; and
(iii) reducing the compound resulting from step (ii) to produce the cis isomer thereof, whereby a cis:trans selectivity of greater than about 90 percent is obtainable.
2. A method of preparing a .Iadd.cis .Iaddend.compound of the formula: ##STR13## wherein R1 is a lower alkyl, lower .[.cylic.]. .Iadd.cyclic .Iaddend.alkyl, .[.lower alkyl.]. lower cyclic alkyl .Iadd.lower alkyl.Iaddend., lower alkenyl or .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.].; R2 is a phenyl which may be substituted with one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, halogen or combinations thereof, and R3 is selected from the group consisting of phenyl-lower-alkyl, thiazoyl lower alkyl which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-4-oxo-1H-tetrazol-1-yl) lower alkyl which can be substituted in the 4-position with a lower alkyl, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl, or combinations thereof; said method comprising:
(i) deprotonating a compound of the following formula: ##STR14## with a non-nucleophilic base to form a deprotonated anion at the 3-position of the piperidine ring;
(ii) reacting said anion with a substituting agent to introduce said .[.Rgroup.]. .Iadd.R1 group .Iaddend.in said 3-position; and
(iii) reducing the compound resulting from step (ii) to produce the .Iadd.cis .Iaddend.compound .[.(1).]. above, .[.thereby obtaining the cis isomer thereof,.]. whereby a cis:trans selectivity of greater than about 90 percent is obtainable.
3. The method of claim 1 or 2, wherein said non-nucleophilic base is a lithium lower alkyl amide.
4. The method of claim 3, wherein said lithium lower alkyl amide is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium tetramethylpiperamide and lithium bis(trimethylsilyl)amide.
5. The method of claim 1 or 2 wherein said substituting agent is an alkylating agent.
6. The method of claim 1 or 2 wherein said deprotonating is carried out in a solvent comprising tetrahydrofuran.
7. The method of claim 5, wherein said alkylating agent is an iodide or tosylate.
8. The method of claim 7, wherein said iodidc is an alkyl iodide.
9. The method of claim 1 or 2, wherein said reducing is by means of a hindered borohydride reducing agent.
10. The method of claim 9, wherein said hindered borohydride reducing agent is selected from the group consisting of lithium triethylborohydride, lithium tri-sec-butylborohydride, .[.or.]. .Iadd.and .Iaddend.lithium hydride 9-ββN-nopolbenzylether adduct.
11. The method of claim 1 or 2, wherein the steps (i) through (iii) are carried out continuously without purification or isolation of intermediates.
12. The method of claim 11, wherein the said steps (i) through (iii) are continuously carried out in the same reactor means.
13. The method of claim 1 or 2, wherein said cis isomer is purified from minor amounts of the trans isomer.
14. A method for preparing a .Iadd.cis .Iaddend.compound of the formula: ##STR15## wherein R1 is a lower alkyl, lower .[.cylic.]. .Iadd.cyclic .Iaddend.alkyl, lower .[.alkyl lower cylic alkyl,.]. .Iadd.cyclic alkyl .Iaddend.lower alkyl, lower alkenyl, or .Iadd.phenyl .Iaddend.lower alkyl .[.phenyl.].; R2 is a phenyl, which may be substituted with one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, halogen or combinations thereof, and R3 is selected from the group consisting of phenyl-lower-alkyl, thiazoyl lower alkyl which can be substituted in the 4-position with a lower alkyl group, (4,5-dihydro-4-oxo-1H-tetrazol-1-yl) lower alkyl which can be substituted in the 4-position with a lower alkyl, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl, halogen or combinations thereof; said method comprising:
(i) reacting H2 NR2 with a compound of the following formula: ##STR16## .Iadd.to form an imine compound of the formula ##STR17##.Iaddend. (ii) deprotonating the compound .[.of formula (2).]. with a non-nucleophilic base to form a deprotonated anion at the 3-position of the piperidine ring;
(iii) reacting said anion with a substituting agent to introduce an R1 group in said 3-position; and
(iv) reducing the compound of step .[.(ii).]. .Iadd.(iii) .Iaddend.to produce the .Iadd.cis .Iaddend.compound .[.(1).]. above, thereby obtaining the cis isomer thereof, whereby a cis:trans selectivity of greater than about 90 percent is obtainable.
15. The method of claim 14, wherein said substituting agent is an alkylating agent.
16. The method of claim 15, wherein said non-nucleophilic base is a lithium lower alkyl amide.
17. The method of claim 14 wherein said compound is reduced by introducing a hindered borohydride reducing agent.
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US5425615A (en) * | 1994-09-30 | 1995-06-20 | All American Transit Parts | Combination folding stair and platform wheelchair lift |
US6531481B2 (en) | 1998-03-10 | 2003-03-11 | Research Triangle Institute | Opiate compounds, methods of making and methods of use |
US6552032B2 (en) | 1998-03-10 | 2003-04-22 | Research Triangle Institute | Opiate compounds, methods of making and methods of use |
US6593348B2 (en) | 1998-03-10 | 2003-07-15 | Research Triangle Institute | Opiate compounds, methods of making and methods of use |
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